This proposal describes a 3 year research training program for the development of an academic career in hematology. The principal investigator (PI) has completed residency training in Internal Medicine and Hematology, and has been newly appointed as an assistant professor of Medicine at the University of Illinois at Chicago. He has ~8 years of training in molecular and cell biology research and an accomplished publication record. He will expand upon his scientific skills through a unique integration of interdepartmental resources. This program will allow the PI to become an accomplished expert in transporter trafficking, as applied to heme biology and hematopoietic disease. Professor Athar Chishti will mentor his scientific development. Dr. Chishti is a recognized leader in the field of red blood cell membrane protein biology, and the biology of PDZ domain-containing proteins, and protein trafficking. He has trained numerous postdoctoral fellows and graduate students. In addition, an advisory committee of highly-regarded medical scientists will provide scientific and career advice on a regular basis. Research will focus on protein trafficking of the newly recognized heme exporter, FLVCR. We have shown that FLVCR membrane function, the export of heme, is required to permit normal erythropoiesis. The membrane expression of FLVCR, similar to other membrane transporters is likely regulated through control of its trafficking to and from the cell surface. Initial evidence suggests this occurs through interactions with a PDZ domain-containing protein. A yeast two hybrid screen using the cytoplasmic tail of FLVCR identified a candidate protein, which contains a PDZ domain. The proposed experiments involve verification of interactions between FLVCR and the candidate protein, and characterization of the interacting protein. In addition the effects of deletions of domains of the interacting protein on FLVCR expression and trafficking in heterologous cells, including polarized cells, will be examined. An overriding aim however, is to determine the role of trafficking on FLVCR heme export function in epithelial and erythroid cell lines. Studies of the relationship between a PDZ domain-containing protein and FLVCR in FLVCR membrane expression and trafficking may be of relevance to a wide range of human diseases, in particular those characterized by hemolysis or cellular iron overload. The University of Illinois provides an ideal setting for training physician-scientists by incorporating expertise from diverse sources. Such an environment maximizes the potential for the PI to establish a scientific niche from which an academic research career can be constructed. Studies of the mechanisms of regulation of expression of the heme exporter, FLVCR may be of relevance to a wide range of human diseases, in particular those characterized by hemolysis, such as Sickle cell disease, thalassemia. and malaria, or by cellular iron overload...